A novel human mutation associates with increased pain threshold and impaired thermoregulation

Pierre Majdalani ^1,2 Shani Biton ¹ Vered Pinsk ³ Zamir Shorer ⁴ Arnon Broides ³ Ruth Defrin ⁵ Raz Zarivach ⁶ Daniela Landau ⁷ Zvia Rudich ⁸ Ruti Parvari ^1,2

¹Faculty of Health Sciences (A.b.), The Shraga Segal Department of Microbiology, Immunology & Genetics, Ben-Gurion University of the Negev, Israel
²National Institute of Biotechnology in the Negev, Ben-Gurion University of the Negev, Israel
³Soroka University Medical Center, Ben-Gurion University of the Negev, Pediatric Outpatient Clinic, Israel
⁴Soroka University Medical Center, Ben-Gurion University of the Negev, Pediatric Neurology Unit, Israel
⁵Sackler Faculty of Medicine and Sagol School of Neuroscience, Tel-Aviv University, Department of Physical Therapy, School of Allied Health Professions, Israel
⁶The Faculty of Natural Sciences and the Ilse Katz Institute for Nanoscale Science and Technology, Ben-Gurion University of the Negev, Department of Life Sciences, Israel
⁷Soroka University Medical Center, Ben-Gurion University of the Negev, Nicu, Israel
⁸Soroka Hospital, Ben-Gurion University of the Negev, Department of Anesthesiology, Israel

Introduction: Congenital insensitivity to pain is a rare autosomal recessive disease, comprises absence of sensation to noxious stimuli. The aim of this study is to identify and characterize the mutation causing congenital insensitivity to pain in two consanguineous Israeli-Bedouin families.

Materials and Methods: Three patients’ medical records were reviewed. Two out of the three patients are siblings. Genomic DNA was extracted from peripheral blood. Chromosomal microarray analysis, exome capture and sequencing were performed. Data was analyzed for quality, exome coverage, and exome-wide SNP/InDel. Basic bioinformatics analysis were performed to search for variations.

Results: We found a new mutation in the PRDM12 gene that was shared homozygously by the three patients of the two families. An additional splice acceptor mutation in an additional gene presented in the two pateints` siblings in a homozygous and heterozygous pattern in the less and more clinically affected patients, respectively. This mutation was demonstrated to affect splicing in patient`s lymphoblsatoid cells, leading to deletion of two exons thus resulting in absence of important domains in the protein. The additional gene is expressed mainly in the CNS and plays a role in modulating pain and temperature via the opioid system. Both mutations` prevelance was 1/240 chromosomes in the healthy Bedouin population.

Conclusion: We presented a new mutation in the PRDM12 gene and a novel mutation in a gene that plays an important role in pain regulation. Identifying and characterization of a new mutation in genes leads to developing a new diagnostic tools, prevention and treatment.